Fungi are known to infect humans, animals, plants and others to cause various diseases. For example, they cause superficial mycosis in various human tissues such as epidermic corneal layers of skins, keratinous tissues such as nails and hairs, and mucosal epitherlia in oral cavities, and cause deep skin mycosis even in deep skin tissues existing in the depth from the body surfaces, for example, causing profound mycosis even in deep tissues in esophagi, internal organs and brains. Typical pathogenic fungi known to infect humans to cause profound mycosis are those of the genera Candida, Cryptococcus and Aspergillus; and typical pathogenic fungi to cause superficial mycosis will be those of the genus Candida that infect skins, oral cavities and vaginas, and those of the genus Trichophyton that infect the skins of hands and feet. Apart from these, there will be many other various fungi to infect animals and plants.
With the rapid progress in studies and developments relating to antibiotics and drugs for chemical therapy and with wide popularization thereof since 1950s, a lot of drugs for curing bacterial infections have been developed. Similarly, much effort has been paid to development of antifungal drugs. However, as compared with the development of antibacterial agents for chemical therapy, there are not so many compounds that are at present put in clinical use. On the other band, compromised hosts with immunity depression are increasing owing to frequent use of antibacterial drugs (antibiotics, chemical therapy agents) in actual clinical sites or caused by malignant tumors, leukemia, organ or bone marrow transplantation, and AIDS (acquired immunodeficiency syndrome), and, as a result, cases with profound mycosis are increasing in these days, and are now problematic.
Typical antifungals that are now used in the actual clinical sites are polyenemacrolides, phloropyrimidines, azoles, etc. They are essentially for external applications for treatment for superficial mycosis, including, for example, various azole-based drugs, and polyenemacrolide-type nystatin, griseofulvin, terbinafine hydrochloride, butenafine hydrochloride and amorolfine chloride. On the other hand, for treatment for profound mycosis that is significantly increasing these days, azole-based fluconazole and itraconazole are much used because of their safety as compared with any other drugs, but these are problematic in that their antifungal spectrum is narrow. Amphotericin B, a type of polyenemacrolide drugs has a broad antifungal spectrum and is highly effective, but it is problematic in point of its toxicity (side effect). Flucytosine, a type of phloropyrimidine drugs is not toxic, but it readily causes fungal tolerance to drugs. Accordingly, at present, only a few drugs that are at present used for treatment for profound mycosis could be on a satisfactory level for medical treatment in point of the antifungal spectrum, the potency and the safety thereof. In addition, fluconazole that is at present the most popular drug for profound mycosis is poorly susceptible to some pathogenic fungi such as Candida glabrata, Candida tropicalis, Candida krusei, and there are appearing some fungi resistant to it. In the clinical sites, therefore, novel antifungal drugs that overcome these problems are much desired.
On the other hand, a test method of scientifically evaluating the usefulness of substances has been established for development of recent antifungal therapies and novel antifungals. The method is with the progress of the studies of the functions and mechanisms of antifungal drugs, and it is desired to develop more effective and safer drugs. From the point of the overcoming the problem with drug-resistant fungi, it is much desired to develop antifungals having a novel function and mechanism.
Further, from the point of safety, fungi are, differing from bacterial (prokaryotic cells), eukaryotic cells like human cells, and therefore, it is necessary to develop compounds that attack and injure specifically (selectively) fungal cells.
Given that situation, a chemical capable of inhibiting the synthesis of essential cell wall constitutive components of fungi, a so-called cell wall polysaccharide synthesis inhibitor, or that is, an antifungal which targets molecules of cell wall polysaccharide synthetase specifically existing in fungi is expected from the viewpoint of the novelty of the function and the mechanism thereof and from the selective toxicity thereof. For polysaccharides that constitute the cell wall of fungi, known are β-glucan, chitin, chitosan and mannan of which β-glucan is an essential constitutive component of the cell wall of fungi, and this is grouped into 1,3-β-glucan and 1,6-β-glucan.
For 1,3-β-glucan synthetase inhibitor, heretofore reported are papracandins (Non-Patent Reference 1), echinocandins (Non-Patent Reference 2), pneumocandins (Non-Patent Reference 3), aculeacins (Non-Patent Reference 4), etc. Recently, caspofungin (Non-Patent Reference 5) and micafungin (Non-Patent Reference 6) have been developed and put on the market. However, these are all only for injections, and a novel antifungal effective in oral administration is desired.
As a 1,6-β-glucan synthetase inhibitor, reported are tricyclic imidazo[1,2-a]pyridine derivatives (Patent Reference 1); but it is necessary to develop a 1,6-β-glucan synthetase inhibitor that exhibits more potent growth inhibition and has a broad spectrum to objective pathogenic fungi.
On the other hand, it is known that imidazopyridine, triazolopyridine, pyrazolopyridine and their derivatives that are bicyclic skeleton-having pyridine derivatives have a pharmacological activity in an extremely broad range; and there are known reports saying that imidazopyrimidine and pyrazolopyrimidine derivatives exhibit an antifungal effect to fungi that causes plant diseases (Patent Reference 2, Non-Patent Reference 7).
Patent Reference 1: Japanese Patent Application No. 2002-022767 (International Patent Application No. PCT/JP03/00912)
Patent Reference 2: WO03/022850
Non-Patent Reference 1: Journal of Antibiotics, Vol. 36, p. 1539 (1983)
Non-Patent Reference 2: Journal of Medicinal Chemistry, Vol. 38, p. 3271 (1995)
Non-Patent Reference 3: Journal of Antibiotics, Vol. 45, p. 1875 (1992)
Non-Patent Reference 4: Journal of Biochemistry, Vol. 105, p. 606 (1959)
Non-Patent Reference 5: Journal of Medicinal Chemistry, Vol. 37, p. 222 (1994)
Non-Patent Reference 6: Journal of Antibiotics, Vol. 52, p. 647 (1999)
Non-Patent Reference 7: Journal of Medicinal Chemistry, Vol. 18, p. 1253 (1975)